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Home / Equine Research Bank / Front Vet Sci / Interleukin-1β in tendon injury enhances reparative ge...
Frontiers in veterinary science2022; 9; 963759; doi: 10.3389/fvets.2022.963759

Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells.

Abstract: Tendon injury in the horse carries a high morbidity and monetary burden. Despite appropriate therapy, reinjury is estimated to occur in 50-65% of cases. Although intralesional mesenchymal stem cell (MSC) therapy has improved tissue architecture and reinjury rates, the mechanisms by which they promote repair are still being investigated. Additionally, reevaluating our application of MSCs in tendon injury is necessary given recent evidence that suggests MSCs exposed to inflammation (deemed MSC licensing) have an enhanced reparative effect. However, applying MSC therapy in this context is limited by the inadequate quantification of the temporal cytokine profile in tendon injury, which hinders our ability to administer MSCs into an environment that could potentiate their effect. Therefore, the objectives of this study were to define the temporal cytokine microenvironment in a surgically induced model of equine tendon injury using ultrafiltration probes and subsequently evaluate changes in MSC gene and protein expression following inflammatory licensing with cytokines of similar concentration as identified . In our surgically induced tendon injury model, IL-1β and IL-6 were the predominant pro-inflammatory cytokines present in tendon ultrafiltrate where a discrete peak in cytokine concentration occurred within 48 h following injury. Thereafter, MSCs were licensed with IL-1β and IL-6 at a concentration identified from the study; however, only IL-1β induced upregulation of multiple genes beneficial to tendon healing as identified by RNA-sequencing. Specifically, vascular development, ECM synthesis and remodeling, chemokine and growth factor function alteration, and immunomodulation and tissue reparative genes were significantly upregulated. A significant increase in the protein expression of IL-6, VEGF, and PGE2 was confirmed in IL-1β-licensed MSCs compared to naïve MSCs. This study improves our knowledge of the temporal tendon cytokine microenvironment following injury, which could be beneficial for the development and determining optimal timing of administration of regenerative therapies. Furthermore, these data support the need to further study the benefit of MSCs administered within the inflamed tendon microenvironment or exogenously licensed with IL-1β prior to treatment as licensed MSCs could enhance their therapeutic benefit in the healing tendon.
Copyright © 2022 Koch, Berglund, Messenger, Gilbertie, Ellis and Schnabel.
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Publication Date: 2022-08-11 PubMed ID: 36032300PubMed Central: PMC9410625DOI: 10.3389/fvets.2022.963759Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates how Interleukin-1β (IL-1β) affects mesenchymal stem cells (MSCs) in tendon repair, by enhancing the expression of reparative genes and proteins. Findings suggest exposing MSCs to IL-1β could improve their therapeutic benefit for tendon healing.

Tendon Injury and MSC Therapy

  • Tendon injuries in horses, despite treatment, tend to have a high chance of reinjury, estimated to be between 50-65% of cases. These high rates present increased health risks for the animal and the associated treatment costs constitute a significant financial burden.
  • Currently, intralesional mesenchymal stem cell (MSC) therapy is employed to improve tissue structure and lower reinjury rates. However, the exact mechanisms employed by MSCs to promote repair are still being researched. The study implies the need for continual evaluation of MSC usage in tendon injuries.

Mesenchymal Stem Cell Licensing

  • Recent studies suggest that MSCs exposed to inflammation (also known as MSC licensing) could have increased remedial effects.
  • However, the application of MSC therapy in an inflamed setting has been hindered by a lack of sufficient data regarding the time-specific cytokine profile in tendon injury. Without knowing the cytokine environment, it’s challenging to expose MSCs to an environment that would potentially enhance their effect by inducing inflammation.

Study Objectives and Findings

  • The study’s focal points were to understand more about the cytokine environment in an equine tendon injury and examine changes in MSC gene and protein expressions following inflammatory licensing with these cytokines.
  • In the induced tendon injury study model, Interleukin-1β (IL-1β) and IL-6 were the main pro-inflammatory cytokines. MSCs were exposed to these cytokines, but only IL-1β induced the upregulation of numerous genes that are beneficial to tendon healing, as identified through RNA-sequencing.
  • Particular genes associated with vascular development, extracellular matrix (ECM) synthesis and remodeling, chemokine and growth factor functions, as well as immunomodulation and tissue reparative genes, saw significant upregulation.
  • Additionally, the protein expression of IL-6, Vascular Endothelial Growth Factor (VEGF), and Prostaglandin E2 (PGE2) increased significantly in the MSCs licensed by IL-1β.

Conclusions and Recommendations

  • These findings can enhance the understanding of the cytokine microenvironment in tendon injuries, aiding the development and timing of regenerative therapies.
  • The data strongly indicates a further exploration into the benefits of administering MSCs into the inflamed tendon microenvironment, or licensing them with IL-1β prior to treatment, as these techniques could potentially enhance their therapeutic effect in tendon healing.

Cite This Article

APA
Koch DW, Berglund AK, Messenger KM, Gilbertie JM, Ellis IM, Schnabel LV. (2022). Interleukin-1β in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells. Front Vet Sci, 9, 963759. https://doi.org/10.3389/fvets.2022.963759

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 9
Pages: 963759
PII: 963759

Researcher Affiliations

Koch, Drew W
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Berglund, Alix K
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Messenger, Kristen M
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
  • Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
Gilbertie, Jessica M
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Ellis, Ilene M
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
Schnabel, Lauren V
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.

Grant Funding

  • K01 OD027037 / NIH HHS
  • T32 OD011130 / NIH HHS
  • T35 OD011070 / NIH HHS

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

This article includes 92 references
  1. Patterson-Kane JC, Firth EC. The pathobiology of exercise-induced superficial digital flexor tendon injury in Thoroughbred racehorses.. Vet J 2009 Aug;181(2):79-89.
    doi: 10.1016/j.tvjl.2008.02.009pubmed: 18406184google scholar: lookup
  2. O'Meara B, Bladon B, Parkin TD, Fraser B, Lischer CJ. An investigation of the relationship between race performance and superficial digital flexor tendonitis in the Thoroughbred racehorse.. Equine Vet J 2010 May;42(4):322-6.
    doi: 10.1111/j.2042-3306.2009.00021.xpubmed: 20525050google scholar: lookup
  3. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon.. Equine Vet J 2012 Jan;44(1):25-32.
    doi: 10.1111/j.2042-3306.2011.00363.xpubmed: 21615465google scholar: lookup
  4. Schnabel LV, Lynch ME, van der Meulen MC, Yeager AE, Kornatowski MA, Nixon AJ. Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons.. J Orthop Res 2009 Oct;27(10):1392-8.
    doi: 10.1002/jor.20887pubmed: 19350658google scholar: lookup
  5. Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, Wang Y. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases.. Nat Rev Nephrol 2018 Aug;14(8):493-507.
    doi: 10.1038/s41581-018-0023-5pubmed: 29895977google scholar: lookup
  6. Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L. Immunological characterization of multipotent mesenchymal stromal cells--The International Society for Cellular Therapy (ISCT) working proposal.. Cytotherapy 2013 Sep;15(9):1054-61.
    doi: 10.1016/j.jcyt.2013.02.010pubmed: 23602578google scholar: lookup
  7. Broekman W, Amatngalim GD, de Mooij-Eijk Y, Oostendorp J, Roelofs H, Taube C, Stolk J, Hiemstra PS. TNF-α and IL-1β-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor.. Respir Res 2016 Jan 11;17:3.
    doi: 10.1186/s12931-015-0316-1pmc: PMC4710048pubmed: 26753875google scholar: lookup
  8. Murphy N, Treacy O, Lynch K, Morcos M, Lohan P, Howard L, Fahy G, Griffin MD, Ryan AE, Ritter T. TNF-α/IL-1β-licensed mesenchymal stromal cells promote corneal allograft survival via myeloid cell-mediated induction of Foxp3(+) regulatory T cells in the lung.. FASEB J 2019 Aug;33(8):9404-9421.
    doi: 10.1096/fj.201900047Rpubmed: 31108041google scholar: lookup
  9. Cassano JM, Schnabel LV, Goodale MB, Fortier LA. Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment.. Stem Cell Res Ther 2018 Apr 3;9(1):82.
    doi: 10.1186/s13287-018-0840-2pmc: PMC5883371pubmed: 29615127google scholar: lookup
  10. Planat-Benard V, Varin A, Casteilla L. MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism.. Front Immunol 2021;12:626755.
    doi: 10.3389/fimmu.2021.626755pmc: PMC8120150pubmed: 33995350google scholar: lookup
  11. Aktas E, Chamberlain CS, Saether EE, Duenwald-Kuehl SE, Kondratko-Mittnacht J, Stitgen M, Lee JS, Clements AE, Murphy WL, Vanderby R. Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect.. J Orthop Res 2017 Feb;35(2):269-280.
    doi: 10.1002/jor.23258pubmed: 27061844google scholar: lookup
  12. Ellis I, Schnabel LV, Berglund AK. Defining the Profile: Characterizing Cytokines in Tendon Injury to Improve Clinical Therapy.. J Immunol Regen Med 2022 May;16.
    doi: 10.1016/j.regen.2022.100059pmc: PMC8932644pubmed: 35309714google scholar: lookup
  13. Morita W, Dakin SG, Snelling SJB, Carr AJ. Cytokines in tendon disease: A Systematic Review.. Bone Joint Res 2017 Dec;6(12):656-664.
    doi: 10.1302/2046-3758.612.BJR-2017-0112.R1pmc: PMC5935810pubmed: 29203638google scholar: lookup
  14. Schulze-Tanzil G, Al-Sadi O, Wiegand E, Ertel W, Busch C, Kohl B, Pufe T. The role of pro-inflammatory and immunoregulatory cytokines in tendon healing and rupture: new insights.. Scand J Med Sci Sports 2011 Jun;21(3):337-51.
    doi: 10.1111/j.1600-0838.2010.01265.xpubmed: 21210861google scholar: lookup
  15. Messenger KM, Wofford JA, Papich MG. Carprofen pharmacokinetics in plasma and in control and inflamed canine tissue fluid using in vivo ultrafiltration.. J Vet Pharmacol Ther 2016 Feb;39(1):32-9.
    doi: 10.1111/jvp.12233pubmed: 25958925google scholar: lookup
  16. Messenger KM, Papich MG, Blikslager AT. Distribution of enrofloxacin and its active metabolite, using an in vivo ultrafiltration sampling technique after the injection of enrofloxacin to pigs.. J Vet Pharmacol Ther 2012 Oct;35(5):452-9.
    doi: 10.1111/j.1365-2885.2011.01338.xpubmed: 21913941google scholar: lookup
  17. Rossard TP. Tumor Necrosis Factor. New York, NY: Nova Biomedical Books; (2009).
  18. Schramme M, Hunter S, Campbell N, Blikslager A, Smith R. A surgical tendonitis model in horses: technique, clinical, ultrasonographic and histological characterisation.. Vet Comp Orthop Traumatol 2010;23(4):231-9.
    doi: 10.3415/VCOT-09-10-0106pubmed: 20585715google scholar: lookup
  19. Schnabel LV, Pezzanite LM, Antczak DF, Felippe MJ, Fortier LA. Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro.. Stem Cell Res Ther 2014 Jan 24;5(1):13.
    doi: 10.1186/scrt402pmc: PMC4055004pubmed: 24461709google scholar: lookup
  20. Mzyk DA, Bublitz CM, Sylvester H, Mullen KAE, Hobgood GD, Baynes RE, Foster DM. Short communication: Use of an ultrafiltration device in gland cistern for continuous sampling of healthy and mastitic quarters of lactating cattle for pharmacokinetic modeling.. J Dairy Sci 2018 Nov;101(11):10414-10420.
    doi: 10.3168/jds.2018-14849pubmed: 30197136google scholar: lookup
  21. Underwood C, Collins SN, van Eps AW, Allavena RE, Medina-Torres CE, Pollitt CC. Ultrafiltration of equine digital lamellar tissue.. Vet J 2014 Nov;202(2):314-22.
    doi: 10.1016/j.tvjl.2014.05.007pubmed: 25439438google scholar: lookup
  22. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function.. Eur Heart J 2012 Apr;33(7):829-37, 837a-837d.
    doi: 10.1093/eurheartj/ehr304pmc: PMC3345541pubmed: 21890489google scholar: lookup
  23. Lee AY, Eri R, Lyons AB, Grimm MC, Korner H. CC Chemokine Ligand 20 and Its Cognate Receptor CCR6 in Mucosal T Cell Immunology and Inflammatory Bowel Disease: Odd Couple or Axis of Evil?. Front Immunol 2013;4:194.
    doi: 10.3389/fimmu.2013.00194pmc: PMC3711275pubmed: 23874340google scholar: lookup
  24. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease.. Cold Spring Harb Perspect Biol 2014 Sep 4;6(10):a016295.
    doi: 10.1101/cshperspect.a016295pmc: PMC4176007pubmed: 25190079google scholar: lookup
  25. Xiang M, Li S. Foxn4: a multi-faceted transcriptional regulator of cell fates in vertebrate development.. Sci China Life Sci 2013 Nov;56(11):985-93.
    doi: 10.1007/s11427-013-4543-8pubmed: 24008385google scholar: lookup
  26. Zhu B, Xue F, Zhang C, Li G. LMCD1 promotes osteogenic differentiation of human bone marrow stem cells by regulating BMP signaling.. Cell Death Dis 2019 Sep 9;10(9):647.
    doi: 10.1038/s41419-019-1876-7pmc: PMC6733937pubmed: 31501411google scholar: lookup
  27. Watanabe K. Prostaglandin F synthase.. Prostaglandins Other Lipid Mediat 2002 Aug;68-69:401-7.
    doi: 10.1016/S0090-6980(02)00044-8pubmed: 12432932google scholar: lookup
  28. Bjørklund G, Svanberg E, Dadar M, Card DJ, Chirumbolo S, Harrington DJ, Aaseth J. The Role of Matrix Gla Protein (MGP) in Vascular Calcification.. Curr Med Chem 2020;27(10):1647-1660.
    doi: 10.2174/0929867325666180716104159pubmed: 30009696google scholar: lookup
  29. Porter S, Clark IM, Kevorkian L, Edwards DR. The ADAMTS metalloproteinases.. Biochem J 2005 Feb 15;386(Pt 1):15-27.
    doi: 10.1042/BJ20040424pmc: PMC1134762pubmed: 15554875google scholar: lookup
  30. Shiomi T, Lemaître V, D'Armiento J, Okada Y. Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases.. Pathol Int 2010 Jul;60(7):477-96.
    doi: 10.1111/j.1440-1827.2010.02547.xpmc: PMC3745773pubmed: 20594269google scholar: lookup
  31. Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration.. Trends Mol Med 2013 Jan;19(1):31-9.
    doi: 10.1016/j.molmed.2012.10.010pubmed: 23182855google scholar: lookup
  32. Nowicki M, Wierzbowska A, Małachowski R, Robak T, Grzybowska-Izydorczyk O, Pluta A, Szmigielska-Kapłon A. VEGF, ANGPT1, ANGPT2, and MMP-9 expression in the autologous hematopoietic stem cell transplantation and its impact on the time to engraftment.. Ann Hematol 2017 Dec;96(12):2103-2112.
    doi: 10.1007/s00277-017-3133-4pubmed: 28956132google scholar: lookup
  33. Jamil S, Mousavizadeh R, Roshan-Moniri M, Tebbutt SJ, McCormack RG, Duronio V, Scott A. Angiopoietin-like 4 Enhances the Proliferation and Migration of Tendon Fibroblasts.. Med Sci Sports Exerc 2017 Sep;49(9):1769-1777.
    doi: 10.1249/MSS.0000000000001294pubmed: 28398948google scholar: lookup
  34. La Paglia L, Listì A, Caruso S, Amodeo V, Passiglia F, Bazan V, Fanale D. Potential Role of ANGPTL4 in the Cross Talk between Metabolism and Cancer through PPAR Signaling Pathway.. PPAR Res 2017;2017:8187235.
    doi: 10.1155/2017/8187235pmc: PMC5274667pubmed: 28182091google scholar: lookup
  35. Pauly S, Klatte F, Strobel C, Schmidmaier G, Greiner S, Scheibel M, Wildemann B. BMP-2 and BMP-7 affect human rotator cuff tendon cells in vitro.. J Shoulder Elbow Surg 2012 Apr;21(4):464-73.
    doi: 10.1016/j.jse.2011.01.015pubmed: 21454098google scholar: lookup
  36. Murray SJ, Santangelo KS, Bertone AL. Evaluation of early cellular influences of bone morphogenetic proteins 12 and 2 on equine superficial digital flexor tenocytes and bone marrow-derived mesenchymal stem cells in vitro.. Am J Vet Res 2010 Jan;71(1):103-14.
    doi: 10.2460/ajvr.71.1.103pmc: PMC4246500pubmed: 20043789google scholar: lookup
  37. Tan SL, Ahmad TS, Ng WM, Azlina AA, Azhar MM, Selvaratnam L, Kamarul T. Identification of Pathways Mediating Growth Differentiation Factor5-Induced Tenogenic Differentiation in Human Bone Marrow Stromal Cells.. PLoS One 2015;10(11):e0140869.
    doi: 10.1371/journal.pone.0140869pmc: PMC4631504pubmed: 26528540google scholar: lookup
  38. Galipeau J. Macrophages at the nexus of mesenchymal stromal cell potency: The emerging role of chemokine cooperativity.. Stem Cells 2021 Sep;39(9):1145-1154.
    doi: 10.1002/stem.3380pmc: PMC8453730pubmed: 33786935google scholar: lookup
  39. Gelse K, Pöschl E, Aigner T. Collagens--structure, function, and biosynthesis.. Adv Drug Deliv Rev 2003 Nov 28;55(12):1531-46.
    doi: 10.1016/j.addr.2003.08.002pubmed: 14623400google scholar: lookup
  40. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis.. J Biol Chem 1995 Nov 10;270(45):27348-57.
    doi: 10.1074/jbc.270.45.27348pubmed: 7592998google scholar: lookup
  41. Kim SW, Lee DW, Yu LH, Zhang HZ, Kim CE, Kim JM, Park TH, Cha KS, Seo SY, Roh MS, Lee KC, Jung JS, Kim MH. Mesenchymal stem cells overexpressing GCP-2 improve heart function through enhanced angiogenic properties in a myocardial infarction model.. Cardiovasc Res 2012 Sep 1;95(4):495-506.
    doi: 10.1093/cvr/cvs224pubmed: 22886775google scholar: lookup
  42. Cui Q, Fu S, Li Z. Hepatocyte growth factor inhibits TGF-β1-induced myofibroblast differentiation in tendon fibroblasts: role of AMPK signaling pathway.. J Physiol Sci 2013 May;63(3):163-70.
    doi: 10.1007/s12576-013-0251-1pubmed: 23371911google scholar: lookup
  43. Severino V, Alessio N, Farina A, Sandomenico A, Cipollaro M, Peluso G, Galderisi U, Chambery A. Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells.. Cell Death Dis 2013 Nov 7;4(11):e911.
    doi: 10.1038/cddis.2013.445pmc: PMC3847322pubmed: 24201810google scholar: lookup
  44. Andersen MB, Pingel J, Kjær M, Langberg H. Interleukin-6: a growth factor stimulating collagen synthesis in human tendon.. J Appl Physiol (1985) 2011 Jun;110(6):1549-54.
    doi: 10.1152/japplphysiol.00037.2010pubmed: 21350025google scholar: lookup
  45. Skutek M, van Griensven M, Zeichen J, Brauer N, Bosch U. Cyclic mechanical stretching enhances secretion of Interleukin 6 in human tendon fibroblasts.. Knee Surg Sports Traumatol Arthrosc 2001 Sep;9(5):322-6.
    doi: 10.1007/s001670100217pubmed: 11685366google scholar: lookup
  46. Legerlotz K, Jones ER, Screen HR, Riley GP. Increased expression of IL-6 family members in tendon pathology.. Rheumatology (Oxford) 2012 Jul;51(7):1161-5.
    doi: 10.1093/rheumatology/kes002pmc: PMC3380247pubmed: 22337942google scholar: lookup
  47. Cook SA, Schafer S. Hiding in Plain Sight: Interleukin-11 Emerges as a Master Regulator of Fibrosis, Tissue Integrity, and Stromal Inflammation.. Annu Rev Med 2020 Jan 27;71:263-276.
    doi: 10.1146/annurev-med-041818-011649pubmed: 31986085google scholar: lookup
  48. Maier R, Ganu V, Lotz M. Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases.. J Biol Chem 1993 Oct 15;268(29):21527-32.
    doi: 10.1016/S0021-9258(20)80573-0pubmed: 8408003google scholar: lookup
  49. Hashimoto G, Inoki I, Fujii Y, Aoki T, Ikeda E, Okada Y. Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165.. J Biol Chem 2002 Sep 27;277(39):36288-95.
    doi: 10.1074/jbc.M201674200pubmed: 12114504google scholar: lookup
  50. Gill SE, Parks WC. Metalloproteinases and their inhibitors: regulators of wound healing.. Int J Biochem Cell Biol 2008;40(6-7):1334-47.
    doi: 10.1016/j.biocel.2007.10.024pmc: PMC2746915pubmed: 18083622google scholar: lookup
  51. Xia W, Szomor Z, Wang Y, Murrell GA. Nitric oxide enhances collagen synthesis in cultured human tendon cells.. J Orthop Res 2006 Feb;24(2):159-72.
    doi: 10.1002/jor.20060pubmed: 16435353google scholar: lookup
  52. Xia W, Wang Y, Appleyard RC, Smythe GA, Murrell GA. Spontaneous recovery of injured Achilles tendon in inducible nitric oxide synthase gene knockout mice.. Inflamm Res 2006 Jan;55(1):40-5.
    doi: 10.1007/s00011-005-0006-4pubmed: 16429255google scholar: lookup
  53. Murrell GA, Szabo C, Hannafin JA, Jang D, Dolan MM, Deng XH, Murrell DF, Warren RF. Modulation of tendon healing by nitric oxide.. Inflamm Res 1997 Jan;46(1):19-27.
    doi: 10.1007/s000110050027pubmed: 9117513google scholar: lookup
  54. Murakami M, Nakatani Y, Tanioka T, Kudo I. Prostaglandin E synthase.. Prostaglandins Other Lipid Mediat 2002 Aug;68-69:383-99.
    doi: 10.1016/S0090-6980(02)00043-6pubmed: 12432931google scholar: lookup
  55. Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases.. Clin Immunol 2006 Jun;119(3):229-40.
    doi: 10.1016/j.clim.2006.01.016pubmed: 16540375google scholar: lookup
  56. Day AJ, Milner CM. TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties.. Matrix Biol 2019 May;78-79:60-83.
    doi: 10.1016/j.matbio.2018.01.011pubmed: 29362135google scholar: lookup
  57. Yang Y, Sun H, Li X, Ding Q, Wei P, Zhou J. Transforming Growth Factor Beta-Induced Is Essential for Endotoxin Tolerance Induced by a Low Dose of Lipopolysaccharide in Human Peripheral Blood Mononuclear Cells.. Iran J Allergy Asthma Immunol 2015 Jun;14(3):321-30.
    pubmed: 26546902
  58. Ruiz M, Toupet K, Maumus M, Rozier P, Jorgensen C, Noël D. TGFBI secreted by mesenchymal stromal cells ameliorates osteoarthritis and is detected in extracellular vesicles.. Biomaterials 2020 Jan;226:119544.
    doi: 10.1016/j.biomaterials.2019.119544pubmed: 31648137google scholar: lookup
  59. Chen P, Farivar AS, Mulligan MS, Madtes DK. Tissue inhibitor of metalloproteinase-1 deficiency abrogates obliterative airway disease after heterotopic tracheal transplantation.. Am J Respir Cell Mol Biol 2006 Apr;34(4):464-72.
    doi: 10.1165/rcmb.2005-0344OCpmc: PMC2644207pubmed: 16388023google scholar: lookup
  60. Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, Baker A, Anand-Apte B. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2.. Nat Med 2003 Apr;9(4):407-15.
    doi: 10.1038/nm846pubmed: 12652295google scholar: lookup
  61. Rauniyar K, Jha SK, Jeltsch M. Biology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels.. Front Bioeng Biotechnol 2018;6:7.
    doi: 10.3389/fbioe.2018.00007pmc: PMC5816233pubmed: 29484295google scholar: lookup
  62. Zhang F, Liu H, Stile F, Lei MP, Pang Y, Oswald TM, Beck J, Dorsett-Martin W, Lineaweaver WC. Effect of vascular endothelial growth factor on rat Achilles tendon healing.. Plast Reconstr Surg 2003 Nov;112(6):1613-9.
    doi: 10.1097/01.PRS.0000086772.72535.A4pubmed: 14578792google scholar: lookup
  63. Liu X, Zhu B, Li Y, Liu X, Guo S, Wang C, Li S, Wang D. The Role of Vascular Endothelial Growth Factor in Tendon Healing.. Front Physiol 2021;12:766080.
    doi: 10.3389/fphys.2021.766080pmc: PMC8579915pubmed: 34777022google scholar: lookup
  64. Pufe T, Petersen WJ, Mentlein R, Tillmann BN. The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease.. Scand J Med Sci Sports 2005 Aug;15(4):211-22.
    doi: 10.1111/j.1600-0838.2005.00465.xpubmed: 15998338google scholar: lookup
  65. Halper J. Advances in the use of growth factors for treatment of disorders of soft tissues. In: Halper J. editor. Progress in Heritable Soft Connective Tissue Disorders. Dordrecht: Springer; (2013). p. 69–76.
  66. Millar NL, Murrell GA, McInnes IB. Inflammatory mechanisms in tendinopathy - towards translation.. Nat Rev Rheumatol 2017 Jan 25;13(2):110-122.
    doi: 10.1038/nrrheum.2016.213pubmed: 28119539google scholar: lookup
  67. Carrade Holt DD, Wood JA, Granick JL, Walker NJ, Clark KC, Borjesson DL. Equine mesenchymal stem cells inhibit T cell proliferation through different mechanisms depending on tissue source.. Stem Cells Dev 2014 Jun 1;23(11):1258-65.
    doi: 10.1089/scd.2013.0537pubmed: 24438346google scholar: lookup
  68. Zhang J, Wang JH. Prostaglandin E2 (PGE2) exerts biphasic effects on human tendon stem cells.. PLoS One 2014;9(2):e87706.
    doi: 10.1371/journal.pone.0087706pmc: PMC3913640pubmed: 24504456google scholar: lookup
  69. Vasta S, Di Martino A, Zampogna B, Torre G, Papalia R, Denaro V. Role of VEGF, Nitric Oxide, and Sympathetic Neurotransmitters in the Pathogenesis of Tendinopathy: A Review of the Current Evidences.. Front Aging Neurosci 2016;8:186.
    doi: 10.3389/fnagi.2016.00186pmc: PMC4977280pubmed: 27555817google scholar: lookup
  70. Cadby JA, David F, van de Lest C, Bosch G, van Weeren PR, Snedeker JG, van Schie HT. Further characterisation of an experimental model of tendinopathy in the horse.. Equine Vet J 2013 Sep;45(5):642-8.
    doi: 10.1111/evj.12035pubmed: 23448172google scholar: lookup
  71. Patterson-Kane JC, Rich T. Achilles tendon injuries in elite athletes: lessons in pathophysiology from their equine counterparts.. ILAR J 2014;55(1):86-99.
    doi: 10.1093/ilar/ilu004pubmed: 24936032google scholar: lookup
  72. Patterson-Kane JC, Becker DL, Rich T. The pathogenesis of tendon microdamage in athletes: the horse as a natural model for basic cellular research.. J Comp Pathol 2012 Aug-Oct;147(2-3):227-47.
    doi: 10.1016/j.jcpa.2012.05.010pubmed: 22789861google scholar: lookup
  73. Kumar V, Abbas AK, Aster JC. Inflammation and repair. In: Kumar V, Abbas AK, Aster JC. editors. Robbins and Cotran Pathologic Basis of Disease. Philadelphia, PA: Elsevier Saunders; (2015). p. 69–111.
  74. Tarafder S, Chen E, Jun Y, Kao K, Sim KH, Back J, Lee FY, Lee CH. Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling.. FASEB J 2017 Sep;31(9):3991-3998.
    doi: 10.1096/fj.201700071Rpmc: PMC5572690pubmed: 28533328google scholar: lookup
  75. Stolk M, Klatte-Schulz F, Schmock A, Minkwitz S, Wildemann B, Seifert M. New insights into tenocyte-immune cell interplay in an in vitro model of inflammation.. Sci Rep 2017 Aug 29;7(1):9801.
    doi: 10.1038/s41598-017-09875-xpmc: PMC5575127pubmed: 28851983google scholar: lookup
  76. Müller SA, Todorov A, Heisterbach PE, Martin I, Majewski M. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering.. Knee Surg Sports Traumatol Arthrosc 2015 Jul;23(7):2097-105.
    doi: 10.1007/s00167-013-2680-zpubmed: 24057354google scholar: lookup
  77. Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells.. Cell Death Differ 2014 Feb;21(2):216-25.
    doi: 10.1038/cdd.2013.158pmc: PMC3890955pubmed: 24185619google scholar: lookup
  78. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells.. Cytokine Growth Factor Rev 2009 Oct-Dec;20(5-6):419-27.
    doi: 10.1016/j.cytogfr.2009.10.002pubmed: 19926330google scholar: lookup
  79. Fan H, Zhao G, Liu L, Liu F, Gong W, Liu X, Yang L, Wang J, Hou Y. Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis.. Cell Mol Immunol 2012 Nov;9(6):473-81.
    doi: 10.1038/cmi.2012.40pmc: PMC4002219pubmed: 23085948google scholar: lookup
  80. Yao Y, Zhang F, Wang L, Zhang G, Wang Z, Chen J, Gao X. Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction.. J Biomed Sci 2009 Aug 20;16(1):74.
    doi: 10.1186/1423-0127-16-74pmc: PMC2739513pubmed: 19691857google scholar: lookup
  81. Kim W, Lee SK, Kwon YW, Chung SG, Kim S. Pioglitazone-Primed Mesenchymal Stem Cells Stimulate Cell Proliferation, Collagen Synthesis and Matrix Gene Expression in Tenocytes.. Int J Mol Sci 2019 Jan 22;20(3).
    doi: 10.3390/ijms20030472pmc: PMC6387004pubmed: 30678291google scholar: lookup
  82. Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W, Roberts AI, Le AD, Shi S, Shao C, Shi Y. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression.. J Immunol 2010 Mar 1;184(5):2321-8.
    doi: 10.4049/jimmunol.0902023pmc: PMC2881946pubmed: 20130212google scholar: lookup
  83. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.. Cell Stem Cell 2008 Feb 7;2(2):141-50.
    doi: 10.1016/j.stem.2007.11.014pubmed: 18371435google scholar: lookup
  84. Bundgaard L, Stensballe A, Elbæk KJ, Berg LC. Mass spectrometric analysis of the in vitro secretome from equine bone marrow-derived mesenchymal stromal cells to assess the effect of chondrogenic differentiation on response to interleukin-1β treatment.. Stem Cell Res Ther 2020 May 20;11(1):187.
    doi: 10.1186/s13287-020-01706-7pmc: PMC7238576pubmed: 32434555google scholar: lookup
  85. Raikin SM, Garras DN, Krapchev PV. Achilles tendon injuries in a United States population.. Foot Ankle Int 2013 Apr;34(4):475-80.
    doi: 10.1177/1071100713477621pubmed: 23386750google scholar: lookup
  86. Rajpar I, Barrett JG. Multi-differentiation potential is necessary for optimal tenogenesis of tendon stem cells.. Stem Cell Res Ther 2020 Apr 9;11(1):152.
    doi: 10.1186/s13287-020-01640-8pmc: PMC7146987pubmed: 32272975google scholar: lookup
  87. Lipman K, Wang C, Ting K, Soo C, Zheng Z. Tendinopathy: injury, repair, and current exploration.. Drug Des Devel Ther 2018;12:591-603.
    doi: 10.2147/DDDT.S154660pmc: PMC5865563pubmed: 29593382google scholar: lookup
  88. Park SH, Lee HS, Young KW, Seo SG. Treatment of Acute Achilles Tendon Rupture.. Clin Orthop Surg 2020 Mar;12(1):1-8.
    doi: 10.4055/cios.2020.12.1.1pmc: PMC7031433pubmed: 32117532google scholar: lookup
  89. Tsekes D, Konstantopoulos G, Khan WS, Rossouw D, Elvey M, Singh J. Use of stem cells and growth factors in rotator cuff tendon repair.. Eur J Orthop Surg Traumatol 2019 May;29(4):747-757.
    doi: 10.1007/s00590-019-02366-xpubmed: 30627922google scholar: lookup
  90. Cho WS, Chung SG, Kim W, Jo CH, Lee SU, Lee SY. Mesenchymal Stem Cells Use in the Treatment of Tendon Disorders: A Systematic Review and Meta-Analysis of Prospective Clinical Studies.. Ann Rehabil Med 2021 Aug;45(4):274-283.
    doi: 10.5535/arm.21078pmc: PMC8435464pubmed: 34496470google scholar: lookup
  91. van den Boom NAC, Winters M, Haisma HJ, Moen MH. Efficacy of Stem Cell Therapy for Tendon Disorders: A Systematic Review.. Orthop J Sports Med 2020 Apr;8(4):2325967120915857.
    doi: 10.1177/2325967120915857pmc: PMC7227154pubmed: 32440519google scholar: lookup
  92. Oreff GL, Fenu M, Vogl C, Ribitsch I, Jenner F. Species variations in tenocytes' response to inflammation require careful selection of animal models for tendon research.. Sci Rep 2021 Jun 14;11(1):12451.
    doi: 10.1038/s41598-021-91914-9pmc: PMC8203623pubmed: 34127759google scholar: lookup

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